Target Analysis of Human MET

Human MET

MET was first discovered as an oncogene. It encodes a tyrosine kinase receptor for hepatocyte growth factor (HGF). The mature MET receptor is structurally distinct from most other RTKs and exists as a heterodimer containing an extracellular α-chain and a transmembrane β-chain, which anchors the kinase domain in its cytoplasmic portion. In normal physiology, the MET signalling pathway regulates many cellular responses including cell proliferation, survival, motility, invasion and morphogenesis. Upon activation via HGF binding and/or receptor overexpression, MET autophosphorylates, recruits adaptor proteins and activates multiple downstream effector proteins and cascades. HGF and MET are expressed in various tissues, but are usually restricted to cells of epithelial and mesenchymal origin. Genetic studies support an essential role for MET during embryonic development and organogenesis. In adults, MET is involved mainly in tissue damage repair and regeneration.

The MET pathway is one of the most frequently deregulated pathways in human cancer and an aberrant MET signaling has been documented in most solid tumors and hematological malignancies. Hence, the HGF/MET axis offers a potentially high-value target for cancer drug development. MET is the driving mutation in hereditary and papillary renal cancer, as well as some glioblastomas, gastric, hepatocellular, and soft tissue cancers and its overexpression is associated with poor prognosis in these patients. The known biological consequences of MET activation are invasion, cellular morphogenesis, motility, metastasis, immortalization, and angiogenesis, and they read like a list of the most undesirable properties associated with cancer. In addition to its own unique effects, MET signaling enhances tumor angiogenesis mediated by the VEGF axis. The response to hypoxia that increases HGF release and MET signaling enhances metastasis in untreated tumors and may be important in the resistance to VEGF-targeted agents in cancer therapy. EGFR, MET inhibitors in combination can have synergistic activity, and simultaneous targeting of MET and VEGF, if achieved in a balanced manner by either a combination of agents or a single dually targeted agent, may offer benefits that exceed the inhibition of either target alone. The preclinical data that support therapeutic approaches for MET inhibition in cancer are both extensive and convincing, offering a compelling rationale for the further exploration of targeting c-MET in patients.

While activation of the MET signaling pathway can result in the abnormal growth and spread of cancerous tumors, MET also plays a critical role in cortical and cerebellar development. Thus MET is also a candidate gene of interest for a broad range of neuropsychiatric disorders with a neurodevelopmental etiology, including autism.

In this report, we analyze the MET gene with respect to its pharamacogenomic properties. The areas of focus include:

• Gene summary
• Orthologs and paralogs
• Alternate transcription
• Expression
• SNP analysis
• Other genetic alterations
• Promoter analysis
• Protein domains
• Disease

Table of Contents

1. Gene Summary - 4

2. Orthologs of MET - 6
 
3. Alternate transcription in MET - 10
  3A. Alternate transcription in humans - 10
  3B. MET expression in normal tissues - 14
  3C. Alternate transcripts of MET in mammalian model organisms - 16

4. Polymorphisms in MET - 17
  4A. MET polymorphisms in humans - 18
  4B. Coding region SNPs- location and type - 19
  4C. Discussion of coding region polymorphisms - 21
  4D. MET polymorphisms with moderate risk and >10% minor allele frequency - 31
  4E. MET polymorphisms in humans - reported in literature - 33
  4G. MET polymorphisms in mouse - 38

5. Other genetic alterations - 39
  5A. Mutations - 39
    5A.1 Somatic mutations in human MET - 39
    5A.2 Germline mutations in MET - 50
  5B. Methylation and acetylation - 55
  5C. Chromosomal aberrations - 56
  5D. miRNA targets in the MET gene - 67

6. Promoter analysis - 70

7. Paralogs - 77

8. Protein family and domain - 79

9. Expression and activity of MET in disease - 82
  9A. MET expression in neoplastic diseases - 84
  9B. MET expression in non-neoplastic diseases - 97

10. References - 102

COPYRIGHT INFORMATION - 128

Executive Summaries and Sample Pages |  Sample Appendix